US3842091A - Dibenzoxirenazepine derivatives - Google Patents

Dibenzoxirenazepine derivatives Download PDF

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Publication number
US3842091A
US3842091A US00291627A US29162772A US3842091A US 3842091 A US3842091 A US 3842091A US 00291627 A US00291627 A US 00291627A US 29162772 A US29162772 A US 29162772A US 3842091 A US3842091 A US 3842091A
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United States
Prior art keywords
dibenz
azepine
acid
compound
dihydro
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Expired - Lifetime
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US00291627A
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English (en)
Inventor
K Kawashima
T Ishiguro
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Chemical Industries Ltd
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Chemical Industries Ltd
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Filing date
Publication date
Priority claimed from JP7697171A external-priority patent/JPS5439390B2/ja
Priority claimed from JP7444872A external-priority patent/JPS5517036B2/ja
Priority claimed from JP7632472A external-priority patent/JPS4931686A/ja
Application filed by Chemical Industries Ltd filed Critical Chemical Industries Ltd
Application granted granted Critical
Publication of US3842091A publication Critical patent/US3842091A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • R stands for a hydrogen atom, a lower alkyl group, a lower alkyl amino lower alkyl group, an aralkyl group, an aryl group or an amino group, have anti-convulsive, anti-epileptic, anti-trigeminal neuralgia and antiarrhythmia activities.
  • the present invention relates to novel dibenzoxirenazepine derivatives having strong anti-convulsive, antiepileptic, anti-trigeminal neuralgia and anti-arrhythmia activities. More concretely, the present invention relates to a compound represented by the following formula (I) N 1 ONHR wherein, R stands for a hydrogen atom, a lower alkyl group, a lower alkyl amino lower alkyl group, an aralkyl group, an aryl group or an amino group.
  • R stands for a hydrogen atom, a lower alkyl group, a lower alkyl amino lower alkyl group, an aralkyl group, an aryl group or an amino group.
  • the lower alkyl group represented by R is exemplified by alkyl such as methyl, ethyl, npropyl or isopropyl.
  • the lower alkyl amino lower alkyl group represented by R is exemplified by dimethylaminopropyl, diethylaminopropyl, dimethylaminomethyl, diethylaminoethyl or dipropylaminopropyl.
  • the aralkyl group represented by R is exemplified by benzyl, phenethyl or henylpropyl.
  • the aryl group represented by R is exemplified by phenyl, tolyl, or xylyl.
  • the compound of the formula (I) can be produced by, for example, the following steps.
  • the compound of the formula (I) wherein R is a lower alkyl group, and aralkyl group or aryl group is produced by reacting a compound represented by the formula (II) (ZONE-R wherein R is a lower alkyl group, an aralkyl group or aryl group with an organic peracid (Step A).
  • an organic peracid is used in an amount of more than about one mole equivalent, more preferably, from one mole equivalent to 20 mole equivalents relative to the compound (II).
  • the said organic peracid is exemplified by aliphatic organic peracids (e.g. performic acid, peracetic acid, perpropionic acid, per-n-butyric acid, perisobutyric acid, p radipic acid, trichloroperacetic acid, trifluoroperacetic acid or monopermaleic acid), or aromatic organic peracids (e.g. perbonzoic acid, m-chloroperbonzoic acid, p-nitroperbenzoic acid or monoperphthalic acid).
  • Step A may be conducted under such conditions that the organic peracid is generated in the reaction system. For instance, it is convenient to employ a combination of (l) e.g.
  • Step (A) preferably proceeds in a conventional solvent which does not hinder the intended reaction, such as halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane), aromatic hydrocarbons (e.g. benzene, toluene or xylene), fatty acids (e.g. acetic acid), ethers (e.g. ethyl ether or tetrahydrofuran), alcohols (e.g. methanol or ethanol), ketones (e.g. acetone or methyl ethyl 'ketone).
  • halogenated hydrocarbons e.g. dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane
  • aromatic hydrocarbons e.g. benzene, toluene or xylene
  • fatty acids e.g. acetic acid
  • ethers e.g
  • the reaction can proceed advantageously by using an acid catalyst, such as sulfuric acid, phosphoric acid, activated alumina, or by adding an organic peracid stabilizer such as unsaturated phosphoric esters (e.g. di-Z-butenyl 2-ethylhexyl phosphate, dioctyl 3- pentenyl phosphate).
  • an acid catalyst such as sulfuric acid, phosphoric acid, activated alumina
  • an organic peracid stabilizer such as unsaturated phosphoric esters (e.g. di-Z-butenyl 2-ethylhexyl phosphate, dioctyl 3- pentenyl phosphate).
  • the reaction is carried out in general at a temperature ranging from l0 C. to 150 C., preferably from 0 C. to C.
  • Step B the reaction is carried out in the absence or in the presence of a solvent such as alcohols (e.g. methanol, ethanol, propanol or pentanol), benzene, toluene, xylene, ethyl ether, chloroform or a mixture of two or more of them.
  • a solvent such as alcohols (e.g. methanol, ethanol, propanol or pentanol), benzene, toluene, xylene, ethyl ether, chloroform or a mixture of two or more of them.
  • the reaction is carried out at a temperature ranging from 10 C. to 200 0., preferably from 0 C. to C.
  • the amine (IV) In the reaction of the amine (IV) with the compound (III) wherein Y is a halogen atom and Z is a hydroxyl group, at least one mole of the amine and not less than 2 moles, preferably 2 moles to 60 moles, of an acid acceptor, respectively relative to one mole of the compound (III), may be employed.
  • an acid-acceptor the amine itself or any other basic substance such as trialkylamine (e.g. triethylamine, trimethylamine, tripropylamine, tributylamine or trihexylamine), alkali carbonate (e.g. sodium carbonate or potassium carbonate) or alkali hydrogen carbonate (e.g. sodium hydrogen carbonate or potassium hydrogen carbonate) may be used.
  • At least one mole of the amine and not less than one mole, preferably one mole to 60 moles, of the acid acceptor, respectively relative to one mole of the compound (III), may be employed.
  • the amine (IV) may be used as a free-form or as an acid-addition salt.
  • the reaction is preferably carried out in the presence of an alkali which makes the amine salt free.
  • alkali are the same as those of the said basic substance.
  • the reaction time is generally about 30 minutes to several hours.
  • the product may be separated through per se conventional manner, eg distillation of the solvent, separation, purification or extraction with an organic solvent (cg. chloroform or ethanol).
  • So-washed solution is dried with sodium sulfate, and concentrated under reduced pressure to leave a dry cystalline substance, which is recrystallized from hexane-benzene (2:1 v./v.) to obtain 2.12 parts by weight of N-propyl-5H-dibenz[b,f] azepine-S-carboxamide (yield: 76.3%). Melting point: 137139 C.
  • reaction tained by, for example, reacting a compound represented by the formula (V) wherein X has the same meaning as defined above with an organic peracid.
  • the reaction may be conducted in a similar manner to the Step A.
  • Another starting compound of the formula (III), in which Y is a halogen atom and Z is a hydroxyl group, is obtained by, for example, allowing a reaction product between a compound (V) and an organic peracid to react with a hydrohalogenic acid.
  • the hydrohalogenic acid is exemplified by hydrochloric acid, hydrobromic acid or hydriodic acid, and is used at least one mole, preferably one mole to 5 moles relative to one mole of the reaction product between a compound (V) and an organic peracid.
  • the reaction is carried out in any solvent which does not hinder the reaction, which is exemplified by aromatic hydrocarbons (e.g. benzene or toluene), ethers (e.g. ethyl ether, tetrahydrofuran or dioxane), esters (e.g. ethyl acetate).
  • aromatic hydrocarbons e.g. benzene or toluene
  • ethers e.g. ethyl ether, tetrahydrofuran or dioxane
  • esters e.g. ethyl acetate
  • the compound (I) is useful as an agent for the treatment of, for example, convulsion, epilepsy, trigeminal neuralgia or errhythmia, and its usual daily dosage for a safe administration to an adult human is in the range of about 200 to 1,500 milligrams in such a form as tablet, powder, granule, capsule, liquid, injection, etc.
  • the reaction mixture is cooled 'with ice, and pH of the solution is adjusted to 5-6 with 1 N NaOH, to 'which is added 10 parts by volume of a 5% aqueous solution of sodium hydrogen sulfite. .
  • pH of the solution is adjusted to 5-6 with 1 N NaOH, to 'which is added 10 parts by volume of a 5% aqueous solution of sodium hydrogen sulfite.
  • parts by volume of a saturated solution of sodium hydrogen carbonate and 10 parts by volume of chloroform are added thereto.
  • the mixture is shaken in a separating funnel, and the chloroform layer is separated, which is shaken with 10 parts by volume of a saturated solution of sodium hydrogen carbonate.
  • the chloroform layer washed with 10 parts by volume of water and dried with anhydrous sodium sulfate.
  • the chloroform is distilled off under reduced pressure at a temperature not higher than C. to leave 1.62 part by weight of residue. Analysis of the residue by nuclear magnetic resonance spectroscopic method shows 31.5% yield of the desired compound. Further, the residue is subjected to column chromatography on 35 parts by weight of silica gel, using a mixed solvent of chloroform-acetone-ethanol 10:2) as the eluent and then the eluate is distilled off, whereby 0.318 part by weight of 1a,10b-dihydro-6H-dibenz[b,f] oxiren[d]azepine-6 carboxamide is obtained. Melting point of the product recrystallized from ethanol is 193 C. (with decomposition).
  • EXAMPLE 2 To 6.2 pants by weight of 5H-dibenz[b,f]azepine-5- carbonyl chloride dissolved in 60 parts by volume of chloroform is added 6.4 parts by weight of m-chloroperbenzoic acid and the mixture is refluxed for 5 hours. To the reaction solution are added 60 parts by volume of chloroform, 35 parts by volume of a saturated sodium hydrogen carbonate solution and 40 parts by volume of 5% sodium hydrogen sulfite. The mixture is sufliciently shaken. The chloroform layer is washed with water and dried over anhydrous sodium sulfate, followed by evaporating off the solvent under reduced pressure.
  • ox1ren[d]-azepine-6-carboxamide la,l0b-d1hydro-6l3I-d1benz[b,f]ox1ren[dlazeplneo 1a,10b-dihydro-6H-dibenzlb,f]oxiren[d] Ethyl acetate- 185-187 carbonyl chlorlde plus hydrazine hydrate. azepine-fi-carboxylic acid hydrazide. chloroform.
  • EXAMPLE 3 In 10 parts by volume of tetrahydrofuran is dissolved in 2 parts by weight of la,1 0b dihydro-6H-dibenz[b,f] oxiren[d]azepine-6-carbonyl chloride obtained in Exam- ON H-R wherein R stands for a hydrogen atom, a lower alkyl group, a lower alkyl amino lower alkyl group, a phenyl C -C alkyl group, a phenyl, tolyl or xylyl group or an amino group or its pharmaceutically acceptable salt.
  • R stands for a hydrogen atom, a lower alkyl group, a lower alkyl amino lower alkyl group, a phenyl C -C alkyl group, a phenyl, tolyl or xylyl group or an amino group or its pharmaceutically acceptable salt.
  • R is a lower alkyl amino lower alkyl group.
  • R is a phenyl, tolyl or xylyl group.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Drying Of Solid Materials (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
US00291627A 1971-09-30 1972-09-25 Dibenzoxirenazepine derivatives Expired - Lifetime US3842091A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP7697171A JPS5439390B2 (enrdf_load_stackoverflow) 1971-09-30 1971-09-30
JP7444872A JPS5517036B2 (enrdf_load_stackoverflow) 1972-07-24 1972-07-24
JP7632472A JPS4931686A (enrdf_load_stackoverflow) 1972-07-28 1972-07-28

Publications (1)

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US3842091A true US3842091A (en) 1974-10-15

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US00291627A Expired - Lifetime US3842091A (en) 1971-09-30 1972-09-25 Dibenzoxirenazepine derivatives

Country Status (13)

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US (1) US3842091A (enrdf_load_stackoverflow)
BE (1) BE789320A (enrdf_load_stackoverflow)
CA (1) CA981667A (enrdf_load_stackoverflow)
CH (2) CH575950A5 (enrdf_load_stackoverflow)
DE (1) DE2246842A1 (enrdf_load_stackoverflow)
DK (1) DK136906B (enrdf_load_stackoverflow)
ES (1) ES407133A1 (enrdf_load_stackoverflow)
FR (1) FR2154714B1 (enrdf_load_stackoverflow)
GB (1) GB1402325A (enrdf_load_stackoverflow)
HU (1) HU164851B (enrdf_load_stackoverflow)
NL (1) NL7213177A (enrdf_load_stackoverflow)
NO (1) NO136495C (enrdf_load_stackoverflow)
SE (1) SE403616B (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6908915B1 (en) * 1999-09-01 2005-06-21 Technion Research & Development Foundation Ltd. Tricyclic compounds and their uses as antiarrhythmic antifibrillatory and defibrillatory agents
AU2002307863B8 (en) * 2001-05-25 2007-10-18 Bial - Portela & Ca, S.A. Method for preparation of 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide and 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide
US20080139807A1 (en) * 2005-01-14 2008-06-12 Portela & C.A.,S.A. Method For Preparation Of 10,11-Dihydro-10-Hydroxy-5H-Dibenz/B,F/Azepine-5-Carboxamide

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4230718A (en) * 1979-01-09 1980-10-28 A. H. Robins Company, Inc. 1-Substituted-3,4-epoxypyrrolidines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH505101A (de) * 1969-03-31 1971-03-31 Ciba Geigy Ag Verfahren zur Herstellung von neuen Azepinderivaten
CH554342A (de) * 1969-06-20 1974-09-30 Takeda Chemical Industries Ltd Verfahren zur herstellung neuer dibenzazepinderivate.

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6908915B1 (en) * 1999-09-01 2005-06-21 Technion Research & Development Foundation Ltd. Tricyclic compounds and their uses as antiarrhythmic antifibrillatory and defibrillatory agents
AU2002307863B8 (en) * 2001-05-25 2007-10-18 Bial - Portela & Ca, S.A. Method for preparation of 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide and 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide
US20080139807A1 (en) * 2005-01-14 2008-06-12 Portela & C.A.,S.A. Method For Preparation Of 10,11-Dihydro-10-Hydroxy-5H-Dibenz/B,F/Azepine-5-Carboxamide
US7834177B2 (en) 2005-01-14 2010-11-16 Bial - Portela & Ca, S.A. Method for preparation of 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide

Also Published As

Publication number Publication date
GB1402325A (en) 1975-08-06
CH575950A5 (enrdf_load_stackoverflow) 1976-05-31
NL7213177A (enrdf_load_stackoverflow) 1973-04-03
FR2154714A1 (enrdf_load_stackoverflow) 1973-05-11
SE403616B (sv) 1978-08-28
CA981667A (en) 1976-01-13
ES407133A1 (es) 1975-10-16
NO136495B (enrdf_load_stackoverflow) 1977-06-06
DK136906C (enrdf_load_stackoverflow) 1978-05-29
FR2154714B1 (enrdf_load_stackoverflow) 1975-11-28
CH578569A5 (enrdf_load_stackoverflow) 1976-08-13
BE789320A (fr) 1973-03-27
DE2246842A1 (de) 1973-04-05
DK136906B (da) 1977-12-12
HU164851B (enrdf_load_stackoverflow) 1974-04-11
NO136495C (no) 1977-09-14

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